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Novel metal polyphenol framework for MR imaging-guided photothermal therapy Gaozheng Zhao, Huihui Wu, Ruilu Feng, Dongdong Wang, Pengping Xu, Peng Jiang, Kang Yang, Zhen Guo, Haibao Wang, and Qianwang Chen ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b16222 • Publication Date (Web): 04 Jan 2018 Downloaded from http://pubs.acs.org on January 4, 2018

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ACS Applied Materials & Interfaces

Novel metal polyphenol framework for MR imaging-guided photothermal therapy Gaozheng Zhao1, Huihui Wu2, Ruilu Feng1, Dongdong Wang1, Pengping Xu1, Peng Jiang1, Kang Yang1, Haibao Wang3*, Zhen Guo2*, and Qianwang Chen1*

1 Hefei National Laboratory for Physical Sciences at Microscale, Department of Materials Science & Engineering & Collaborative Innovation Center of Suzhou Nano Science and Technology, CAS High Magnetic Field Laboratory, University of Science and Technology of China, Hefei, 230026, China, E-mail: [email protected]; 2 Anhui Key Laboratory for Cellular Dynamics and Chemical Biology, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China, E-mail: [email protected]; 3 Radiology Department of the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China, E-mail: [email protected]； G. Zhao, H. Wu, R. Feng, contribute equally to the manuscript.

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Abstract Phothermal therapy has received increasing attention in recent years as a potentially effective way for treatment of cancer. In pursuit of a more biocompatible photothermal agent, we utilize bio-safe materials-ellagic acid (EA), polyvinyl pyrrolidone (PVP) and iron element as the building blocks, and successfully fabricate homogeneous nanosized Fe-EA framework for the first time by a facile method. As expected, the novel nano-agent exhibits no obvious cytotoxicity and good hemocompatibility in vitro and in vivo. The microenvironment-responsiveness to both pH and hydrogen peroxide makes the NPs biodegradable in tumor tissues and the framework should be easily cleared by the body. Photothermal potentials of the nanoparticles are demonstrated with relevant feature of strong NIR light absorption, fairish photothermal conversion efficiency, good photothermal stability, and in-vivo photothermal therapy also achieved effective tumor ablation with no apparent toxicity. On the other hand, it also exhibit T2 MR imaging ability originated from ferric ions. Our work highlights the promise of Fe-EA framework for imaging-guided photothermal therapy. Keywords: metal-polyphenol, MRI, photothermal therapy, microenvironment-responsiveness, MOFs

Introduction Cancer has been one of the most fatal diseases in this world and great efforts have been made to develop various treatment methods conquering cancer1-6. For those traditional cancer treatments, such as chemotherapy and radiotherapy, bottleneck has been encountered owing to a variety of insurmountable shortcomings, for example, chemotherapy could cause serious side effects with


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almost indiscriminative killing of both cancerous and healthy tissues and may result in low therapeutic efficacy due to multidrug resistance7-8. Thus new types of potentially effective treatment approaches are emerging as alternatives for tumor treatment2, 4, 6, 9, such as photothermal therapy (PTT). Photothermal therapy is a hyperthermia-driven therapeutic methodology that employs heat converted by photoabsorbers from light absorption to “cook” cancer cells10. Due to its minimal side effects and high effectiveness, PTT has become an increasingly attractive approach for targeted and efficient ablation of cancer cells, and in this system, photoabsorbers, usually called photothermal agents (PTA), play a vital role. After several decades of development, photothermal agents gather a great deal of members which could be mainly divided into four kinds: organic compounds (e.g., indocyanine green (ICG)11, polydopamine12 and polypyrrole13), noble metal nanoparticles (NPs) (e.g., Au nanostructure14, Pd nanosheets15, Ag nanopaticles16), carbon-based

materials

(e.g.,

carbonnanotubes17,graphene18,

carbonnanoparticles19),

semiconductor nanostructures (e.g., Cu2−xSe20, W18O4921, MoS222, WS223). And the exploration for further discovery of novel biocompatible photothermal agents is still ongoing10, 24-26. There are many requirements for a qualified photothermal agent such as strong near-infrared (NIR) absorbance, high photothermal conversion efficiency, good photostability, etc.20, to which the biosafety concerns are paramount priority. Although tremendous experiments on the toxicity of these photothermal agents have been investigated in vitro and in vivo, most of them are in very preliminary stage and long-term biosafety evaluation is extremely rare27-29. The biosafety issues are still ambiguous, especially those nano-agents composed of toxic elements such as organic dyes, semiconductor nanostructures, and potential unknown toxicity in complicated biological environments30-32 may hamper the further clinical use. Faced with this situation, building



photothermal agents with good biocompatible ingredients may be an effective solution. Even if the nanoagents are partially retained or degraded within the body, hazards can be relatively reduced to a much lower level. On the other hand, integrating imaging modality into PTT would provide assistance for better therapeutic planning and monitoring of therapeutic responses10. Ellagic acid (EA), abundant in fruits and nuts, are often used as a food additive and cosmetic ingredient without particular dosage limitations33. Experiments also reveal high dose of oral administration to mice for several month didn’t show toxicity33-34, so it could be regarded as an excellent biocompatible material. Recently, Caruso and his colleges reported hollow capsules of metal–TA (tannic acid) coordination complex, by assembling a variety of metal ions with TA on various substrates for drug delivery, magnetic resonance imaging and positron emission tomography35-37, and the coordination between catechol group and metal ions could be theoretically extended to EA. Herein, homogeneous nanosized Fe-EA framework was fabricated for the first time by a facile and green synthetic method through successful coordination between ferric ions and the catechol group of EA. The characteristic black color of Fe-EA framework derived from the ligand to metal charge transfer band impart the nanoparticles photothermal effect expectedly, and in-vivo photothermal therapy achieved effective tumor ablation. This potential photothermal agent, composed of biocompatible components, exhibit no obvious toxicity, and good hemocompatibility in vitro and in vivo. Combined MRI ability derived from ferric ions, an imaging-guided novel theranostic system was proposed.

Experimental section


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Materials. Ferric trichloride hexahydrate (FeCl3•6H2O, 99.0%), poly(vinylpyrrolidone) (PVP, K-30) were purchased from Shanghai Chemical Reagent Company (Shanghai, China). poly(vinylpyrrolidone) (PVP, K16-18) were purchased from Innochem Co. Ltd. (Beijing, China) and Alfa Aesar Company (Shanghai, China). Ellagic acid (96%) was purchased from Aladdin Industrial Corporation (Shanghai, China). All the above chemicals were used without further purification. Synthetic method. Typically, solution A was prepared as followed: 34mg ellagic acid was dissolved by 10ml NaOH aqueous solution (0.0225M) containing 0.2g PVP. Solution B: 13.5mg FeCl3.6H2O was dissolved by 10mL distilled water containing 0.2g PVP. Then solution A was added to solution B dropwise at room temperature under vigorous stirring, and the solution immediately turned into black. Afterwards, 0.5 g PVP were dissolved into the above solution and the solution was transferred into a 50 mL capacity Teflon autoclave after stirring for 10 min at room temperature. The sealed vessel was then heated at 130oC for 4h before it was cooled to room temperature. The resulting precipitate was centrifuged and washed several times with ethanol and distilled water, finally dried in an oven at 60 oC. Characterization. Field emission scanning electron microscopy (FE-SEM) images were carried out on a JEOL JSM-6700 M scanning electron microscope. Transmission electron microscopy (TEM) images were perfomed on a Hitachi H7650 transmission electron microscope with an accelerating voltage of 200 kV. Powder X-ray diffraction (XRD) patterns obtained were on a Japan Rigaku D/MAX-cAX-ray diffractometer equipped with Cu Ka radiation over the 2θ range of 10-70°. X-ray photoelectron spectroscopy (XPS) measurements were collected on a VGESCALAB MKII X-ray photoelectron spectrometer with an MgKa excitation source (1253.6



eV). The concentration of Fe element was measured by an Optima 7300DV inductively coupled plasma-atomic emission spectrometer (ICP-AES). Ultraviolet-Visible (UV-Vis) Absorption Spectra were measured on a ultraviolet-visible absorption spectrometer (TU-1810DSPC) with the wavelength region between 400-1000 nm. The size distribution and zeta potential were measured by the dynamic laser light scattering (Beckman Coulter Delsa Nano C and Malvern Zetasizer Nano ZS). FTIR spectrum was determined using a Magna-IR 750 spectrometer in the range of 500–4000 cm−1 with a resolution of 4 cm−1. Specific surface areas were calculated from the results of N2 physisorption at 77 K (Micromeritics ASAP 2020) by using the BET (Brunauer–Emmet–Teller) and the pore volume and pore size were calculated according to BJH (Barrett–Joyner–Halenda) formula applied to the adsorption branch. The distribution of the Fe, O, C, N elements were characterized using a scanning transmission electron microscopy (STEM, JEM2100F). In vitro and in vivo MRI measurements. The Fe-EA nanoparticles with different Fe concentrations (0.0625, 0.125, 0.25, 0.5, 1mM) characterized by ICP-AES results were dispersed in PBS solution, and the relaxation properties of the Fe-EA aqueous solution were measured with a clinical magnetic resonance (MR) scanner (GE Signa HDxt 3.0 Tesla MRI system). T1-weighted MR images were taken by using a saturation recovery spin-echo sequence (TE=10 ms, TR=4000, 2000, 1000, 500, 200, 100 ms，respectively). T2*-weighted images were also obtained by Carr-Purcell-Meiboom-Gill method with the RARE sequence using the parameter of TR=120, TE=2.328, 6.112, 9.896, 13.68, 17.46, 21.24 ms, the filp angle = 30o, bandwidth = 31.25Hz, FOV 180×180 mm2, slice thickness = 3mm without gap. For in vivo MRI, BALB/c mice (Shanghai SLAC Laboratory Animal Co., Ltd.) with xenografted tumors were employed. All the animal experiments were performed with approval from the Animal Care Committee of University of


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Science and Technology of China and the Ethical Committee of the Experimental Animal Center of Anhui Medical University. Before tail intravenous injection of Fe-EA nanoparticles (4 mg/mL in PBS, 100µL), mice were anesthetized intraperitoneal injection of 10% chloral hydrate (3.0 g per kg body weight). MR imaging were attained at preinjection, 10 min, 30 min and 24 h post-injection of Fe-EA nanoparticles. Biodistribution measurements in major organs. To determine the biodistribution of our nanoparticles in major organs (tumor, liver, spleen, lung, kidney and heart), 4T1 breast cancer bearing mice (n = 3) were euthanatized after 24h tail intravenous injection of nanoparticles. Next, the collected organs were wet-weighted and digested with aqua regia under heating for 2 h, and Fe contents were analyzed using ICP-AES. A control group (also three mice) without injection of nanoparticles were also disposed with a similar procedure to exclude the endogenous Fe amounts in different organs. Photothermal effect measurements. 1.0 mL of aqueous solution containing the Fe-EA nanoparticles (0.025,0.05, 0.1, 0.2 mg/mL) was placed in a cuvette and then irradiated with the NIR laser (808 nm, 2W/cm2) for 10 min. Temperature of the aqueous solution was measured with a digital non-contact infrared thermometer at selected time intervals (30 s). The control group of pure H2O was also measured under the same conditions. Temperature elevation of different concentration of the nanoparticles after being immersed in PBS solution (pH 5.0) for 24h was also measured. Thermographs were recorded with an infrared thermal camera (ICI7320, Infrared Camera Inc.) as a function of irradiation time with 1 min gap. Pulsed irradiation was carried out for five cycles with 2 min irradiation followed by a 2 min cooling period. In vitro cellular toxicity test. The vitro cytotoxicity was investigated to evaluate whether the



Fe-EA nanoparticles were suitable for biomedical application. HeLa cells were seeded in a 96-well plates at 104 cells per well in 100µL of complete medium, and cultured in a 5% CO2 atmosphere at 37℃ for 12 h. Afterwards, 100 µL of freshly complete medium containing Fe-EA nanoparticles were added to each group to get a final concentration of 150, 75, 50, 25µg/mL respectively, and then incubated again in 5% CO2 at 37℃for 24 h. Cells were rinsed with PBS for three times and the cell viabilities (%) were detected by the standard MTT assay. The phototoxicity was also measured by a similar procedure but after the adding of Fe-EA nanoparticles, the cells were exposed to 808 nm laser with power density of 1W/cm2 for 5 min, and then incubated again in 5% CO2 at 37℃for 24 h. Intracellular degradation behavior of Fe-EA nanoparticles. Typically, Hela cells were cultured with Fe-EA NPs which is similar to the procedure of cytotoxicity test above, after incubation durations for 24h, the cells were harvested, fixed, and sectioned for Bio-TEM characterization. Hemolysis test. Blood was obtained from BALB/c mice (Shanghai SLAC Laboratory Animal Co., Ltd.) and anticoagulated with potassium oxalate. The red blood cells (RBCs) were isolated from serum by centrifugation at 2000 rpm for 5 min and washed twice with PBS solution, then RBCs were resuspended in PBS solution. 0.5 mL of the diluted RBCs suspension was added to 0.5 mL of the Fe-EA suspension in PBS solution with a final nanoparticle concentration of 6.25, 12.5, 25, 50, 100, 200, 400 µg/mL. PBS buffer and distilled water were used as the negative control (0% hemolysis) and the positive control (100% hemolysis), respectively. After incubation for 2h, the tubes were centrifugated at 5000 rpm for 5 minutes. Each group consisted of three test tubes. Next, absorbance values at 541 nm of the supernatant fluids were measured by UV-vis


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spectrophotometry. The hemolysis rate (HR) was calculated using the mean value for each group as follows: HR (%) = (Dt - Dnc)/(Dpc - Dnc) × 100%, where Dt is the absorbance of the testing sample, and Dpc and Dnc are the absorbance of the positive control and the negative control, respectively38. In Vivo Anticancer Activity. Twenty BALB/c mice (Shanghai SLAC Laboratory Animal Co., Ltd.) were subcutaneously injected in the rightside of their back with 4T1 breast cancer cells. After the tumor sizes reached about a volume of about 300mm3. the mice were randomly divided into four groups with different treatments (control, NIR, NPs and NIR+NPs, n= 5 for each group) and start therapy procedure. Control group mice were only injected with 100µL PBS buffer, while the NIR group mice were injected with 100µL PBS buffer and irradiated by laser (1W/cm2) at the tumor nodules at 24h post-injection. NPs group mice were injected with 100µL PBS buffer containing 0.4mg NPs, NIR+NPs group mice were injected with 100µL PBS buffer containing 0.4mg NPs and irradiated by laser (1W/cm2) at the tumor nodules at 24h post-injection. The treatment operation was repeated every 3 days and on day 12, after 4 therapy sessions, the mice were euthanized and the tumors were dissected. Tumor weight was measured at the time of sacrifice. Tumor dimensions were measured with a caliper every 3 days after administration. and the tumor volume was calculated according to the equation39: tumor volume= tumor length× tumor width2/2. Blood analysis. Healthy female BALB/c mice intravenously injected with Fe-EA NPs (0.6 mg per mouse) were sacrificed at 7, 15 days for blood collection. Untreated healthy mice were used as the control. Blood levels of White blood cells (WBC), Red blood cells (RBC), Hemoglobin (HGB), Hematocrit (HCT), Mean corpuscular volume (MCV), Mean corpuscular hemoglobin



(MCH), Mean corpuscular hemoglobin concentration (MCHC), and platelets of control and Fe-EA NPs treated mice were measured. Serum biochemistry data including blood urea nitrogen (BUN) levels and liver function markers such as Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), and Aspartate aminotransferase (AST), were also measured. Statistic was based on 3 mice per data point. Reference normal ranges of hematology data of healthy female Balb/c mice were obtained according to the previous report40.

Results and discussions

Figure 1. (a) Synthetic process of Fe-EA nanoparticles. (b) SEM image and (c) TEM image of Fe-EA nanoparticles. (d) TEM, dark-field STEM images and EELS elements mapping of the nanoparticles with well-distributed Fe, C, N, O elements. Characterization. As a derivative of catechol, ellagic acid (EA) has two catechol group at opposite ends of the molecule, and both could coordinate with various metal ions, therefore it’s an possible organic ligand to build metal-organic frameworks. For conveniently being introduced into our pre-designed system, EA was dissolved in sodium hydroxide solution with a molar ratio of 1:2 and thus deprotonated, and the concentration of the alkaline solution we adopted was much lower


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than the value in industrial purification of EA for fear of damage to the lactone bond of the molecule. After dissolution in sodium hydroxide solution, the pH of the EA alkaline solution was around 7.5 as measured by the pH test paper. Upon addition of the yellow EA solution to FeCl3 aqueous solution, the color immediately turns black which proved the instant coordination between Fe3+ and catechol group of EA molecule. The black precursor was speculated as one-dimensional coordination polymer nanodots as illustrated in Figure S1. The precursor was further processed under hydrothermal condition at the temperature of 130 oC, and finally nanoparticles of different shapes were formed at different reaction conditions (Figure S4(a) and (b)). Considering the excellent thermal stability of ellagic acid which begins to degrade at nearly 400 oC41, we deduce ellagic acid exsiting in the NPs should still remain undamaged. Great efforts were taken to decrease the size of Fe-EA nanoparticles for further biomedical application, including adjustment of reaction time, surfacants, reactants ratios and etc.. Finally, nanosized Fe-EA framework was obtained. Figure 1(b) and (c) show the SEM and TEM results: it can be seen that homogeneous nanoparticles (NPs) with rhombohedral morphology were obtained, and mostly the length of the longer diagonals of the rhombohedron were no more than 300nm. The dynamic light scattering (DLS) also revealed that the mean diameter of the NPs was about 240nm (Figure 2(c)). Typical X-ray diffraction (XRD) patterns in Figure 2(a) revealed the as-prepared nanoparticles were crystalline, and zeta potential of the sample dispersed in the deionized water was also measured by DLS with the value of -21.8mV (Figure S2). The X-ray photoelectron spectroscopy (XPS) measurement was carried out with the peak at 738, 536.6, 294 eV in XPS spectra, demonstrating existence of Fe, O, C elements (Figure 2(b)). The elemental analysis using inductively coupled plasma-atomic emission spectrometry (ICP-AES) showed



Fe-EA NPs contained 11% iron element (w/w).

Figure 2. Characterization of Fe–EA nanoparticles. (a) X-ray diffraction (XRD) patterns of Fe-EA nanoparticles. (b) X-ray photoelectron spectroscopy pattern of Fe-EA nanoparticles. (c) Hydrodynamic size distribution of the nanoparticles. (d) Fourier transform infrared spectroscopy (FTIR) patterns of ellagic acid, the precursor and Fe-EA nanoparticles. Fourier transform infrared spectroscopy (FTIR) are applied to investigate the structure and composition of the Fe-EA NPs. As illustrated in Figure 2(d)，compared with pure EA, the disappearance of an characteristic absorption band at 3557 cm-1 (the stretching mode of OH groups in the catechol group42) of the precursor and the Fe-EA NPs revealed successful coordination between catechol group and ferric ions. The infrared bands at 1698 cm-1 (C=O stretching), 1196-1 and 1058 cm-1 (ester linkage of C–O stretching) of pure EA42 demonstrated the existence of the lactone bond while these bands still remained in Fe-EA NPs but were slightly shifted to 1697, 1183, 1069 cm-1 respectively due to the interaction between EA and ferric ions. The bands of Fe-EA NPs at 1600-1450 cm-1 are due to aromatic rings. FTIR results demonstrated


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formation of coordination bond and existence of the lactone bond within Fe-EA NPs. Dark-field STEM and EELS mapping of the particles clearly show the spatial distributions of the Fe, C, N, O elements in the nanoparticle (Figure 1(d)). Fe, O, N elements are uniformly distributed and matching fairly well with the NPs, while the left part of C element intensity of the nanoparticle is a little strengthened due to the influence of carbon membrane. The well-distributed elements mapping combined with the rhombohedron-shaped morphology revealed the Fe-EA system should be single component. Nitrogen adsorption-desorption isotherm results indicated

that

as-synthesized Fe-EA NPs exhibited an average pore size of ~2.1nm (Figure S3(b)). The Brunauer-Emmett-Teller (BET) surface area of Fe-EA NPs was only 27.41 m2g-1, and we speculated it might be the macromolecule PVP reducing the surface area, which was also found in our previous experiment, and the N element revealed by EELS mapping could only be originated from PVP, confirming the existence of the macromolecule either in the pore or on the surface of our NPs. As for the percentage of EA incorporated into the NPs, Fe(III)-polyphenol coordination complexes could form mono-, bis-, tris-coordination under different conditions35, while mono-coordination couldn’t form valid dimensional frameworks. As mentioned above, Fe-EA contained 11% iron element measured by ICP-AES, once tris-coordination happened, mass fraction of EA was calculated to be 89% with simultaneously no PVP incorporating, which is contradictory to the practical situation. So Fe(III)-EA form bis-coordination with a molar ratio of 1:1 between ferric ions and EA in our system, and the percentage of EA is calculated as about 60% (w/w) based on Fe element amount measured by ICP-AES. In conclusion, we think we successfully fabricated bis-coordinated Fe-EA framework with nanoporous structure. A variety of metal-EA coordination crystals (denoted as M-EA, M= Mn, Zn,



Fe) were also synthesized through similar procedure (Figure S4), and these NPs with crystalline framework structure had potentials to be extended to other applications such as electrocatalysis and batteries43-44.

Figure 3. MRI contrast effect. (a) Concentration-dependent relaxation rates over Fe concentration and T2*-weighted MR images of Fe-EA nanoparticles immersed in (a) PBS solution (pH 7.4) for 24h and (b) PBS solution (pH 5.0) for 24h. (c) Biodistribution of Fe-EA nanoparticles in tumor and major organs of 4T1-tumor-bearing mice at 24 h after intravenous injection of NPs. (d) T2 -weighted MR images of the rat (d) before and (e) 10, (f) 30 min and (g) 24 h after intravenous injection of NPs. MRI effect and biodistribution. As reported in previous reports, plenty of FeIII-containing MOFs could be used as T2 contrast agents (CA)6, 45, so an MRI experiment was carried out to examine the feasibility of using Fe-EA NPs as MRI contrast agents. The NPs were dispersed in PBS solutions with different pH values for one day (0.01 M, pH 7.4 and pH 5.0) and was then measured by a 3T MR scanner. At pH 7.4, the longitudinal (r1) relaxivity couldn’t be measured


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while the transverse (r2) relaxivity value was 24.62 mM−1s−1, when the pH was adjusted from 7.4 to 5.0, positive contrast effect could be detected with r1 value of 0.3675 mM−1s−1which was comparable to MnO NPs in early reports46, while the transverse relaxivities (r2) also rose to 61.14 mM−1s−1. As for the contrast effect, even the r1 value of Fe-EA NPs at pH 5.0 didn’t show any comparability with FDA-approved T1 CA (Gd-DTPA, r1 =4-5 mM−1s−1) or most of reported T1 contrast agents47-49, rendering it unsuitable for T1 CAs, but r2 of Fe-EA NPs are of the order of 60 mM−1s−1 at acidic environment,as much as the values of r2 in many reported T2 CAs50-52, such as the commercial T2 CA Combidex (65 mM−1 s−1), which can be considered as sufficient for in vivo use50. High r2/r1 ratio (>8) results in T2-dominated contrast, so the Fe-EA could serve as a T2-weighted contrast agent. In-vivo MRI experiments were also carried out. Compared to the preinjection MR image, T2-weighted images at tumor sites (the red dashed circles) became darker after injection and got the strongest effect at 24h as illustrated in Figure 3(d-e). The mice were then sacrificed for detecting the biodistribution of Fe-EA NPs in different organs, which also demonstrated the exsistence of Fe-EA in tumors. The results above indicated Fe-EA could enter the tumor sites through enhanced permeability and retention (EPR) effect and serve as a T2-weighed contrast agent. Actually, as we mentioned above, Fe(III)-EA form bis-coordination, and theoretically would not respond to mildly acid environment36. But the TEM results revealed that the nanoparticles got a little broken under pH 5.0 (Figure S5), and that’s the reason for MR contrast enhancement: as the EA molecule dissociated, the direct water coordination with the paramagnetic Fe3+ centers contributes to T1 inner-sphere relaxivity according to Solomon-Bloembergen-Morgan (SBM) theory53-54, imparting our NPs weak positive contrast effect. As for the T2 enhancement, we



speculate that the dissociated Fe-EA complex may glue the nanoparticles together as illustrated in Figure S4, and thus T2 contrast effect got enhanced due to size increase of the nanoparticles55. Intracellular degradation behavior of Fe-EA nanoparticles. The possible intracellular degradation of Fe-EA nanoparticles in HeLa cells was investigated, and we found the nanoparticles partially decomposed after incubation for 24h as illustrated in Figure S7. As was discussed before, mildly-acidic environment might result in partial degradation, however, the morphology change seemed a little different from the one in acidic PBS solution, and relevant literature56 inspired us to investigate the potential effect of hydrogen peroxide (H2O2) on the biodegradation. One of distinct feature in tumor tissues is the elevated level of hydrogen peroxide (H2O2) with about 100µM concentration during tumor immortality, proliferation and metastasis57. Fe3+-containing complex, or MOFs58-59 have already been widely reported as the hydrogen peroxide catalyst towards H2O2, so Fe-EA NPs may also act as catalase. Color fading of Fe-EA NPs suspended in H2O2 solution (100mM) was found with obviously generated bubbles of O2 in contrast with the control group (Figure S8(c)), and the reduction in absorbance over time also reflected the disassembly of the Fe-EA frameworks and the NPs finally degraded completely after 16h at this high concentration of H2O2 (Figure S8(a)). 100µM concentration of H2O2 similar to the condition in tumor cells was also employed and the absorbance of Fe-EA NPs at 410nm in deionized water will maintain steady until H2O2 was added, and this progress was relatively much slower (Figure S8(b)). The above experiments demonstrated H2O2-stimulated degradation in tumor cell environment. We deduce the disassembly behavior of Fe-EA nanoparticles in H2O2 might be derived from the electron transfer during catalysis: in the process of catalyzing H2O2, Fe3+ in the matrix will firstly oxidize H2O2 to O2 with itself becoming Fe2+, and then Fe2+ will


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again become Fe3+. The electron transfer involved in the catalytic progress may affect the coordination between the Fe3+ and catechol group, thus EA is dissociated from the NPs. In brief, we think pH and H2O2-responsiveness of Fe-EA nanoparticles could account for the intracellular degradation behavior. It’s reasonable to deduce Fe-EA NPs can degrade into small molecules, and should be easily cleared by the body60.

Figure 4. (a) Absorbance curve of Fe-EA aqueous solution; the inset shows the photogragh of aqueous solution of Fe-EA NPs before and after irradiation for 10min. (b) Temperature elevation of water and Fe-EA aqueous dispersions of different concentration (25, 50, 100, and 200 µg/mL) under 808 nm laser irradiation with a power density of 2 W/cm2 for 10 min. (c) The change of IR thermal images of water and Fe-EA aqueous dispersion (100 µg/mL,3mL) over time under irradiation. (d) Plot temperature change (∆T) after 10 min irradiation versus the concentration of the nanoparticles immersed in water and PBS solution (pH 5.0) for 24h. Photothermal effect of the NPs. It is anticipated that black color of Fe-EA framework derived from the ligand to metal charge transfer (LMCT) band may impart our NPs photothermal effect26,



which drive us to investigate their photothermal effects. As is showed in Figure 4(a), the NPs show a wide absorbance band from visible to near-infrared (NIR) region and have strong absorbance at 808nm. Aqueous dispersion of Fe-EA NPs with different concentrations was exposed to 808 nm NIR light with a power density of 2W/cm2 for 10 min and demonstrated a significant temperature increase by 43.2, 33.3, 24 and 11.6 oC for concentration of 200, 100, 50, 25 µg/mL respectively, and water vapor droplets were observed on the wall of the cuvette as shown in the inset of Figure 4(a). In contrast, the temperature increment of water was only 2.2 oC under the same condition. The difference was quite visually conspicuous in infrared (IR) thermal imaging between water and Fe-EA NPs aqueous dispersion (100 µg/mL) as a function of NIR irradiation time in Figure 4(c). Although mildly acid environment may reduce absorbance as illustrated in Figure S5, incomplete degradation in acid condition wouldn’t influence the photothermal effect to a great extent. As is shown in Figure 4(d), temperature increment was decreased in PBS solution (pH 5.0) for 24h compared with the one in neutral water but still have decent effect. While the degradation of NPs in H2O2 (100µM) would be a relatively slow process, which wouldn’t influence the photothermal effect to a great extent over a period of time. c was calculated as about 17.6% (Figure S10), which exhibited comparable performance to some photothermal agents reported before, such as Au nanorods (21%)20, Au shells (13%)20, Cu2−xSe nanoparticles (22%)20. Remarkably, absorbance at 808nm at the same mass concentration was superior to plenty of the previous reported black-colored photothermal agents such as carbon nanospheres61, PEGylated nanographene sheets18, that’s the main reason why it exhibited good temperature elevation effect. Photostability was also measured with no noticeable particle aggregation observed after irradiation for 30 min (Figure S9(b)), suggesting good dispersion


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stability. Pulsed irradiation for five cycles (2 min irradiation followed by a 2 min cooling period) also did not significantly change photothermal performance of these nanoparticles as illustrated in Figure S9(a). In conclusion, our Fe-EA framework was demonstrated a potential photothermal agent with strong NIR light absorption, fairish photothermal conversion efficiency, and good photothermal stability. Moderate-temperature hyperthermia (42−45°C for 15−60 min) or high-temperature hyperthermia (> 50°C for > 4−6 min) for effectively killing cancer cells62 could easily be reached even at low concentrations for our NPs based on animal heat of 37oC, which means the photothermal therapy potentials in vivo.

Figure 5. (a) Cell viability of as-prepared Fe-EA solution with and without NIR irradiation at various concentrations incubated for 24h. (b) Percentage of hemolysis of RBCs incubated with Fe-EA NPs at different concentrations ranging from 6.25 to 400 µg/mL for 2 h. (c) Tumor growth curves of different groups of tumor-bearing mice after treatments every 3 days for 12 days. (d)



Average weights of tumors of each group at the end of different treatment. (e) Photographs of two mice with the top one from NIR group and the bottom one from NPs+NIR group after 2 irradiation. (f) Photographs of the dissected tumors from different mice groups at day 12 after treatments.

Table 1. The parameters of complete blood panel test and serum biochemistry assay of control group and experimental groups. Reference ranges of hematology data of healthy female Balb/c mice were obtained from the previous report40. Statistic was based on 3 mice per data point. In vivo studies on photothermal therapy. Cell viability of the NPs with and without NIR irradiation at various concentrations was demonstrated in Figure 5(a), the cytotoxicity of NPs were relatively low even at even high concentration of 150 µg/mL. While once the laser irradiation was performed on the cells, obvious inhibitation effect on the cells was observed as a concentration-dependent manner. Hemolysis test (Figure 5(b)) was also investigated with only 1.67% hemolytic rate at 400 ug/mL, conforming to the requirements of the hemolysis test for medical materials38. Complete blood panel test and serum biochemistry assay was also carried out to further investigate the long-term toxicology. From the results in Table 1, the measured parameters of complete blood panel test and serum biochemistry assay all fell within normal


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ranges, which could evidence negligible in-vivo toxicity of the Fe-EA nanoparticles at the tested dose within 15 days. The in-vitro and in-vivo experiments above testify the intrinsic good biocompatibility and phototoxicity for photothermal therapy. Finally, in vivo antitumor experiments were carried out to demonstrate the photothermal therapy effect. Tumor-bearing mice were then randomly divided into four groups, i.e., control group, NIR group, NPs group, NPs + NIR group. For tumor therapy, 100 uL of PBS solution or the one containing 0.4mg Fe-EA NPs were injected into tail-vein, After 24h, tumors were irradiated by 808nm laser with the power density of 1W/cm2 for 5min, and a repeated operation was performed every 3 days. After a process of a 12-day long treatment, Both the tumor size of the NIR group and the NPs group showed similar growing speed and final size to the control group, indicating the laser irradiation or Fe-EA itself wouldn’t effectively inhibit the tumor growth. But when both were applied to the mice, therapeutic effect was obvious with almost no tumor growth. The weight and size contrast of final dissected tumors of different groups (Figure 5(d) and (f)) also proved the successful photothermal ablation of tumor. It’s also apparent in the visual observation as illustrated in Figure 5(e), after two treatment cycle, one mouse of the NIR group has only a little inflammation at the tumor sites while one of the NPs+NIR group got burned black at the tumor sites, which was the scorched tissues derived from local hyperthermia. No apparent toxicity was observed during the therapy process. The in vivo experiments demonstrated the Fe-EA framework could serve as an excellent photothermal agent.

Conclusions In conclusion, a novel photothermal agent is constructed based on low toxic materials including ellagic acid, polyvinyl pyrrolidone (PVP) and iron element for the first time by a facile method. As



expected, the novel nano-agent exhibits no obvious toxicity and good hemocompatibility in vitro and in vivo. Photothermal tests demonstrate the novel iron polyphenol framework have strong NIR light absorption, fairish photothermal conversion efficiency, good photothermal stability, and in-vivo photothermal therapy achieved effective tumor ablation with no apparent toxicity during the therapy. Moreover, the Fe3+-containing nanosized coordination crystals could also play the role of a T2 contrast agent with pH-activated amplification of MRI contrast effect. The pH- and hydrogen peroxide-responsiveness makes the NPs biodegradable in tumor tissues and the NPs should be easily cleared by the body theoretically. Our work highlights the promise of the biocompatible Fe-EA framework for imaging-guided photothermal therapy. It is worth mentioning that a variety of metal-EA frameworks may have prospect for extended applications in other fields.

Author contributions G.Z. and Q.C. conceived and designed the experiments; G.Z., H.W., R.F. and D.W. performed the experiments; P.X., P.J., K.Y. contributed to the data analyses and discussion; G.Z., H.W., R.F. analysed the data and wrote the paper. All authors discussed the results and commented on the manuscript.

Supporting Information. TEM image of the precursor; zeta potential distribution of Fe-EA nanoparticles; nitrogen adsorption-desorption isotherms curves and the corresponding pore size distribution of Fe-EA nanoparticles; SEM images of Fe-EA nanoparticles, Mn-EA nanorods and Zn-EA nanoparticles; pH-responsiveness of Fe-EA nanoparticles revealed by TEM graph and UV-Vis spectra; Bio-TEM image of Fe-EA nanoparticles taken up by HeLa cells; H2O2-responsiveness of Fe-EA


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nanoparticles; Fe-EA aqueous dispersion irradiated for five cycles and for 30min; calculation of photothermal conversion efficiency.

Acknowledgments The work was supported by the National Natural Science Foundation of China, 21571168(Q. W. Chen), The Most Grant 2016YFA0101202 (Z. Guo), U1232211 (Q. W. Chen), 31501130 (J. Zhou), CAS/SAFEA international partnership program for creative research teams and CAS Hefei Science Center (2016HSC-IU011), Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology (2016FXCX005).

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